Public health efforts and current antiobesity agents have not controlled the increasing epidemic of obesity. This disorder is increasingly prevalent in industrialized nations because of the abundance of food and the reduced activity levels that accompany the movement of populations from rural to urban settings. Obesity is loosely defined as an excess of body fat over that needed to maintain health.
Obesity is associated with increased morbidity and mortality. Detrimental effects of obesity on health include an increased risk of cardiovascular disease and the associated conditions of hypertension, diabetes, and hyperlipidemia. Millions of people are clinically obese and, in view of the deleterious effects of obesity on health, would benefit from treatment. Additionally, many people, although not clinically obese, can improve their health and well-being by losing weight.
The pathogenesis of obesity is multifactorial and includes the control of feeding behavior, mechanisms of fat storage, the components of energy intake and expenditure, and genetic and psychological influences. Likewise, the treatment of obesity is generally multifactorial. Unfortunately, the mechanisms of fat storage and genetic influences are not, generally speaking, amenable to treatment. Moreover, the control of feeding behavior and psychological influences require prolonged treatment. In addition, although the components of energy intake and expenditure are treatable, many obese individuals are resistant to or incapable of engaging in activities which significantly increase their energy expenditure. Therefore, controlling energy intake is an attractive approach for the treatment of obesity.
Various drugs and drug classes are known to be weight loss and antiobesity agents. These drugs consist of biological path way affecting agents such as 1) central nervous system agents that affect neurotransmitters or neural ion channels; 2) leptin/insulin/central nervous system pathway agents; 3) gastrointestinal-neural pathway agents; 4) agents that may increase resting metabolic rate (“selective” β-3 stimulators/agonist, uncoupling protein homologues, and thyroid receptor agonists); and 5) other more diverse agents. These suppressants, however, typically do not create a true feeling of satiation, such as that brought on by a “full” stomach and/or they cause undesirable side-effects, such as anxiety, and hyperactivity and may have adverse side effects.
Amphetamines (dextroamphetamine) have been used as weight loss and anti-obesity drugs, but can cause unacceptable tachycardia and hypertension. They also have a high rate of abuse potential. Other sympathomimetic adrenergic agents, including phentermine, benzphetamine, phendimetrazine, mazindol, and diethylpropion, may have adverse cardiovascular side effects, and their indicated use is only short-term (12 weeks), In 2000, the appetite suppressant phenylpropanolamine was removed from United States market because of unacceptable risks of stroke, especially in adult women. Other weight loss agents, such as orlistat and sibutramine, also can have adverse side effects. For example, orlistat use frequently results in adverse events including flatus, oily stools, fecal urgency or fecal incontinence, and abdominal pain, particularly among patients who do not follow the recommended low-fat diet. Further, daily multivitamin supplementation is recommended to prevent the potential of impaired absorption of fat-soluble vitamins (A, D, E, and K) that may theoretically occur with long-term use. The use of sibutramine may increase blood pressure and heart rate, and its use is contraindicated in patients with uncontrolled hypertension, CHD, cardiac dysrhythmias, congestive heart failure, or stroke.
The sensation of satiety as a means of suppressing of appetite is well known in the art and is linked to both obesity treatment and effecting weight loss. For example, U.S. Pat. No. 5,336,486 to Acharya et al. describes the false sensation of satiety induced by filling the stomach with heavy digestible vegetable fibers. Consuming large amounts of fiber, however, requires the patient to expel large quantities of fiber which can cause gastrointestinal discomfort. Others are unable tolerate such high volumes of fiber for other reasons. To diminish the discomfort caused by a full stomach which retains vegetable fibers for a period of time higher than is normal, diet recipes based on vegetable fibers have been refined by the addition of easily digestible products with a low number of calories. See U.S. Pat. No. 5,063,073 to Kratochvil; U.S. Pat. No. 5,654,028 to Christensen et al.; and U.S. Pat. No. 6,426,077 to Grace et al. U.S. Pat. Nos. 5,405,616 and 6,103,269 to Wounderlich et al. describe a material composed of gelatin or collagen hydrolysate, one or more active agents and one or more excipients (i.e., plasticizers, odorants, etc.). The material is prepared as a solution or suspension and then freeze-dried to obtain a solid material. The solid material can be administered as a powder, tablet or capsule. When the dried polymeric material comes in contact with the aqueous medium of the stomach, it first becomes swollen in a few minutes and then is dissolved, resulting in a solution that will not interfere with the emptying of the gastrointestinal tract.
Low caloric products for controlling body weight can be obtained by using collagenic biopolymers, such as: soluble collagen, gelatin or collagen hydrolysate. See U.S. Pat. Nos. 5,100,688; 5,211,976; 5,219,599; 5,665,234; 5,665,419. Commercial products, such as “Dietary Supplement—CALORAD®”, produced by EYI—Essentially Yours Industries, Inc.—USA, have been used for weight loss control and also as a muscular stimulant, as well as an aid for osteoporosis and for arthritis treatment.
None of these drugs and materials, however, has provided a satisfactory means for control of obesity or to induce weight loss with adequate safety for the user.
Absorbent materials for water and aqueous media, including fluids secreted by the human body, are well known in the literature. These materials are typically polymer-based and are produced in the form of powders, granules, microparticles or fibers. Upon contact with an aqueous medium, these polymeric materials swell by absorbing the liquid phase into their structure without dissolving. A “hydrogel” is a polymeric material which has the ability to absorb water and swell. If the water absorbency is more than 20 g water per 1 g of dried polymer, the material is referred to as a “superabsorbent polymer” (SAP). The swelling of these materials in the stomach can cause a sensation of satiety (i.e., full stomach). The sensation of satiety as a means of suppressing appetite is well known in the art and has been used to treat obesity and/or induce weight loss.
Polymeric hydrogels have also been used for controlled drug delivery, particularly for extended release and/or delayed release formulations. In pharmaceutical applications, the drug is typically dispersed within the polymeric material. The rate of release of the drug is dependent on the rate of diffusion of the drug from the hydrogel and/or the rate of degradation of the polymer material. The oral administration of drugs generally uses one of two classes of hydrogels a) those which release drug in the stomach and b) those which release drug in the small intestine or other locations such as the oral cavity, duodenum, etc. The use of hydrogels for the controlled release of active agents, using the “full stomach” principle, has been described in U.S. Pat. No. 3,574,820 to Johnson et al.; U.S. Pat. No. 4,264,493 to Battista; U.S. Pat. No. 4,758,436 to Caldwell et al.; U.S. Pat. No. 5,614,223 to Sipos; U.S. Pat. No. 6,319,510 to Yates; U.S. Pat. No. 6,476,006 to Flashner-Barak et al.; and U.S. Pat. No. 6,485,710 to Zuckerman.
The stomach produces a gastric secretion that is an aqueous medium containing water, hydrochloric acid, pepsin and mucus (polysaccharide biogel). This medium has a pH of 1-3 and contains pepsin proteolytic enzyme. The small intestine secretes an aqueous medium with a chemical composition more complex than that of the stomach. It is characterized by pH of 5-9 and displays biodegradative enzymatic activity in both proteins and polysaccharides. Hydrogels, which are designed to function in the stomach, must be able to (1) swell in acid aqueous media and maintain its volume for a sufficient amount of time to induce therapeutically relevant effects; and (2) be easily eliminated once its function has been fulfilled, to avoid obstruction of the intestinal or gastric tract and to avoid the generation of toxic byproducts.
Unfortunately, many hydrogels that could be used for therapeutic purposes including weight loss and obesity treatment do not swell or swell poorly in the acidic pH of the stomach. Park et al. demonstrated that the swelling ratio of the poly(acrylamide-co-acrylic acid) was dependent on the pH of the medium. At a pH of around 5 the hydrogel showed maximum swelling. The poly(acrylamide-co-acrylic acid) showed repeated swelling and shrinking by alternating the medium pH between 1.2 and 7.5, and the changes in swelling ratio was quite fast occurring in a matter of minutes (Park et al., J Biomater Sci Polym Ed., 11(12), 1371-80 (2000)). Peppas et al. describe copolymers of methacrylic acid (MAA) and 2-methacryloxyethy 1 glucoside (MEG), have pH dependent swelling, with a transition between the swollen and the collapsed states occurred at a pH of 5. The swelling ratios of the hydrogels increased at pH values above 5 (Peppas et al., J. Biomater. Sci. Polymer Edn, Vol. 13, No. 1, pp. 1271-1281 (2002)).
U.S. Pat. No. 5,876,741 to Ron et al describes hydroxypropyl cellulose (HPC) hydrogels crosslinked with adipic acid exhibiting a swelling curve with minimal response at pH<5.0 and a significant response for pH>5.0. This HPC hydrogel crosslinked with adipic acid exhibited nearly ideal results with zero water absorbance at pH<5.0, moderate swelling for 5<pH<7 and over 20 fold swelling for pH>7.
There exists a need for methods to induce swelling of polymeric hydrogels in the low acidity of the stomach for the treatment of obesity and other gastric disorders.
It is therefore an object of the present invention to provide methods to induce satiation and reduce appetite utilizing mechanical and physiological means for the treatment of obesity and other gastric disorders.